Stable antifungal capsule formulation

ABSTRACT

In accordance with the present invention an antifungal capsule formulation providing enhanced stability for antifungal agents subject to oxidative degradation, e.g. nystatin, is disclosed. The new formulation comprises an antifungal agent, in an amount of from about 0.1 to about 50 percent by weight of the total formulation; and a nonaqueous carrier, throughout which said agent is uniformly dispersed. 
     Additionally, an antifungal capsule formulation is disclosed wherein thixotropic properties are imparted to the drug carrier system by addition of a gelling agent, such as silicon dioxide. Such thixotropic properties are desired to promote and prolong adhesion of the drug system to the vaginal mucosa in the treatment of vaginal fungal invections. 
     A low temperature method for fabricating capsules employing such a formulation is also disclosed, said method comprising forming a slurry of the antifungal agent and a nonaqueous liquid carrier, adding a gelling agent, if desired, to the so-formed slurry sufficient to form a thixotropic gel, and encapsulating said gel.

FIELD OF THE INVENTION

The present invention pertains to an antifungal dosage form providingenhanced stability for sensitive antifungal agents, and moreparticularly concerns a capsule formulation, preferably containingnystatin, and methods for its use and manufacture.

BACKGROUND OF THE INVENTION

Antifungal agents may be administered in a variety of dosage forms suchas creams or ointment, tablets, capsules and suppositories. For example,tablets, suppositories and capsules containing one or more antifungalagents are widely used intravaginally for.the treatment of vaginalcandidiasis. Retention of the tablet, capsule or suppository in thevagina and stability of the medicinal agent, during and aftermanufacture, are of primary importance in the success of such treatment.

Nystatin, for example, has a high degree of sensitivity to heat, oxygen,moisture and extremes in pH. This is due to the highly unsaturatednature of the nystatin molecule. Inactivation of amorphous nystatinoccurs even at room temperature and below when subjected to an oxygensource. Elevated moisture conditions and elevated temperatures compoundthe degradation process. Further, it is believed that once oxidationbegins it cannot be stopped, even by storage at -20° C.

Solid nystatin intravaginal tablets typically comprise the medicament,solid binders and about 6 percent by weight of water. The water content,as well as elevated temperatures used during the fabrication of suchtablets, can significantly reduce the activity of the drug. Further,premature expulsion of the hard tablet from the vaginal tract can occur.

Jackson et al. U.S. Pat. No. 4,542,020 discloses long-lasting adhesiveantifungal suppositories comprising an antifungal agent, e.g. nystatin,together with a hydrocolloid and a low melting suppository base. Thesesuppositories melt at body temperature, releasing the drug-containinghydrooolloid which adheres to the vaginal membrane to provide a uniformdistribution of the drug at the site of.the infection. However, thewater soluble or hydratable nature of the hydrocolloid can adverselyaffect the drug's shelf life by allowing and/or contributing tooxidative degradation.

Riley Jr., et al. U.S. Pat. No. 4,551,148, discloses a sustained releasevaginal delivery system providing a more uniform release of themedicament over an extended period. In this system, a non-lipoidalinternal phase containing the antifungal agent is suspended within thelipoidal external phase. The internal phase actually comprises smalldrug-containing packets which are diffused throughout the externalphase. The external phase in turn provides adhesion to the vaginalmembrane at the site of infection. The internal phase disclosed fornystatin, however, contains 60 percent by weight of water, which againcan significantly degrade the activity of the nystatin over time.

Leigh et al. U.S. Pat. No. 4,291,062, discloses pharmaceuticalcompositions for the skin, containing urea, designed to provide goodstability and a smooth texture. These compositions comprise amedicament, e.g. nystatin, presented as small particles coated with awax; an inclusion compound of urea with a straight-chain aliphaticcompound; an inert soluble powder; and an inert carrier into which theaforementioned components are suspended. During the formation of theseskin treatment compositions, however, the medicament is subjected to acomplex process which includes exposure to temperatures of 60° C. andabove during the wax-coating procedure.

An antifungal capsule formulation, for use in oral or vaginal capsules,providing enhanced stability for moisture or oxygen sensitive antifungalagents and, in the case of the vaginal capsule formulation, goodadhesion to the vaginal membrane. A method for fabricating such capsuleswould be useful additions to the art.

SUMMARY OF THE INVENTION

In accordance with the present invention a capsule formulation providingenhanced stability for antifungal or antibacterial agents subject tooxidative and hydrolytic degradation, e.g. nystatin, is disclosed. Thenew formulation comprises, for example, an antifungal agent, in anamount of from about 0.1 to about 50 percent by weight of the totalformulation; and a nonaqueous carrier, throughout which said agent isuniformly dispersed.

A method for fabricating capsules avoiding high temperature exposure isalso disclosed, said method comprising forming a slurry of theantifungal agent in a nonaqueous liquid and encapsulating said slurry.This process is carried out at or below human body temperature and in asubstantially dry and controlled room temperature environment.Optionally, a gelling agent can be added to the so-formed slurry wherethixotropic properties are required, as in the case of the vaginalcapsule.

DETAILED DESCRIPTION OF THE INVENTION

The improved antifungal capsule formulation of the present inventionprovides enhanced stability for an antifungal agent by protecting thedrug from oxygen and moisture. Thus, a drug such as nystatin, which ishighly sensitive to heat, oxygen and moisture, has a substantiallygreater shelf life, and thereby greater efficacy after months ofstorage, when fabricated into the formulation of the present invention.In fact, while nystatin in solid vaginal tablets exhibits potency dropsof 10-15 percent at room temperature in 3 months and 20-30 percent at40° C., nystatin stabilized by the present formulation maintains about98-99 percent of its potency after 3 months storage at 40° C. and nosignificant loss following storage at ambient room temperature forperiods up to 9 months.

The formulation of the present invention, suitable for oral andintravaginal dosage forms, employs a nonaqueous carrier which may be inthe form of a liquid or a thixotropic gel. While thixotropic propertiesare desirable for the vaginally inserted dosage forms, thixotropy isoptional for the orally ingested dosage form. A typical thixotropic gelcarrier is one that sets in the form of a gel (20,000 to 40,000centipoise viscosity) but will liquify at room temperature uponapplication of shear (1000 to 5000 centipoise viscosity). The nonaqueouscarrier may comprise a nonaqueous liquid surfactant, such as a sorbitanmono-9-octadecenoate poly(oxy-1,2-ethanediyl) derivative (e.g. TWEEN 80;Atlas Company); an oleaginous liquid, such as mineral oil or a vegetableoil; or, a hydrogenated fat (e.g. Gelucire; Gattefosse Co.) or a mixtureof any two or more of these nonaqueous materials. When a thixotropic gelcarrier is required, the hydrogenated fat may be employed or a gellingagent such as silicon dioxide or fumigated silicon dioxide (e.g. Aerosil200; Degussa Company) can be added to one of the nonaqueous liquids. Thepreferred nonaqueous carrier for an oral capsule in accordance with thepresent invention is mineral oil and the preferred carrier for thevaginal capsule is a thixotropic gel comprised of mineral oil andfumigated silicon dioxide.

These nonaqueous carriers have been found extremely effective inprotecting the antifungal or antibacterial agents from the deleteriouseffects of oxygen and moisture and thereby seem to render the drugs lesssusceptible to degradation from the elevated temperatures as well. Atthe same time, the thixotropic properties of the gel carrier employed inthe vaginal capsule provide adhesion of the formulation to vaginalmucosa.

The nonaqueous carrier, exclusive of the antifungal agent, typicallycomprises from about 90 to about 100 percent by weight and preferablyfrom about 96 to about 100 percent by weight of the nonaqueous liquidsurfactant.

The gelling agent, when used, is typically present in the carrier,exclusive of the antifungal agent, in an amount of from about 0 to about10 percent by weight of the total carrier and preferably in an amount offrom about 1 to about 2 percent by weight.

Alternatively, the nonaqueous carrier may comprise from about 90 toabout 100 percent by weight of a hydrogenated fat.

The capsule formulation of the present invention will also include oneor more antifungal agents, preferably nystatin, dispersed throughout thecarrier system in sufficient quantities to maintain an effectiveconcentration for sufficient periods of time so as to produce adequatekill of, for example, C. albicans. Thus, the capsule formulation willprovide from about 25,000 to about 1,000,000 and preferably from about75,000 to about 500,000 USP Nystatin units which may be administered upto two times a day or any convenient regimen, such as one capsule 1 or 2times a day.

Other antifungal agents which may be incorporated into the presentformulation include but not limited to amphotericin B, miconazole,ketoconazole, econazole or griseofulvin and antibiotics such aspenicillins, cephalosporins, etc. which are degraded by oxidative and/orhydrolytic routes.

An antifungal capsule in accordance with the present invention comprisesthe above-described capsule formulation encapsulated in any suitablegelatin shell. The antifungal capsule can be administered orally orintravaginally and a water-soluble, soft gelatin shell is preferred forintravaginal administration.

A preferred vaginal antifungal capsule in accordance with the presentinvention will comprise from about 2 to 4 percent by weight of theformulation of nystatin, from about 94 to about 97 percent by weight ofthe formulation of mineral oil, from about 1 to about 2 percent byweight of the formulation of silicon dioxide and be encapsulated in asoft, water-soluble, gelatin shell.

A preferred oral capsule formulation in accordance with the presentinvention will comprise from about 15 to 20 percent by weight ofnystatin, from about 73 to 84 percent by weight of mineral oil, and fromabout 1 to 2 percent by weight of silicon dioxide.

To treat vaginal fungal infections, e.g. vaginal candidiasis, inaccordance with the present invention, the above-described antifungalcapsule is inserted into the vaginal cavity of a human female. Upondissolution of the shell the drug-containing thixotropic gel is releasedand adheres to the vaginal mucous membrane by reason of its thixotropyproviding release of the drug in that area.

Also, in accordance with the present invention is the low temperaturemethod for fabrication of the antifungal capsules. This methoddrastically improves the product in that it avoids exposure of the drugto temperatures above human body temperature thereby substantiallyminimizing oxidative and hydrolytic degradation.

To carry out present methods a suitable amount of the desired antifungalagent, or agents, is added to and mixed with a nonaqueous liquid carrierso that a slurry is formed. Thereafter, the gelling agent, when used, isadded to the slurry so that a carrier/drug thixotropic gel forms uponsetting. The so-formed system is finally encapsulated, preferably in awater-soluble, soft gelatin shell. The method should be carried out in alow humidity, controlled room temperature environment. To fabricateformulations using hydrogenated fat carriers, the fat should be heatedto about human body temperature prior to addition of the drug therein.

The following working examples represent specific embodiments of thepresent invention, however, the scope of the present invention is notmeant to be limited by the details described therein. In all of theexamples, the percentage values in the stability tables are expressed asa percentage of the initial potency.

EXAMPLE 1

An antifungal capsule formulation in accordance with the presentinvention having the following composition was prepared as describedbelow.

    ______________________________________                                        Ingredient              Amount (g)                                            ______________________________________                                        Nystatin* (100,000 USP units)                                                                         160                                                   Mineral Oil, USP        7,720                                                 Fumigated Silicon dioxide                                                     (Aerosil 200)           120                                                   TOTAL                   8,000  g                                              ______________________________________                                         *Actual weight dependent on assay                                        

To 7,720 grams of mineral oil (USP) was added 160 grams of nystatinpowder having a particle size of about 1 to 50 microns. At roomtemperature (˜20° C.) the drug was thoroughly dispersed in the oil toform a slurry using a standard homogenizer. Slowly, 120 grams of thefumigated silicon dioxide was added to the slurry and uniformlydispersed. The so-formed mixture was stored at controlled roomtemperature for about 60 minutes to form a thixotropic gel.

Using a Brookfield LVt viscometer with spindle #3, the viscosity of thegel was tested and the results are summarized below.

    ______________________________________                                        Viscosity (measured at 25° C.)                                                 RPM   CPS                                                             ______________________________________                                                0.3   112,000                                                                 0.6   59,400                                                                  1.5   28,560                                                                  3.0   16,800                                                          ______________________________________                                    

The formulation was thereafter sencapsulated in soft, water-soluble,gelatin shells to form 8,000 vaginal capsules, each capsule containing1000 mg of the formulation.

EXAMPLE 2

An antifungal capsule formulation in accordance with the presentinvention having the following composition was prepared as described inExample 1.

    ______________________________________                                        Ingredient              Amount (g)                                            ______________________________________                                        Nystatin* (100,000 USP units)                                                                         160                                                   TWEEN 80 (Sorbitan mono-9-                                                                            7,720                                                 octadecenoate poly(oxy-1,2-                                                   ethanediyl) derivative)                                                       Fumigated Silicon dioxide                                                     (Aerosil 200)           120                                                   TOTAL                   8,000  g                                              ______________________________________                                         *Actual weight dependent on assay                                        

The formulation ws stored at controlled room temperature for 60 minutes.The viscosity results using Brookfield LVt viscometer with spindle #3are summarized below.

    ______________________________________                                        Viscosity (measured at 25° C.)                                                 RPM   CPS                                                             ______________________________________                                                0.3   68,000                                                                  0.6   36,000                                                                  1.5   19,000                                                                  3.0   12,400                                                          ______________________________________                                    

This formulation was thereafter encapsulated in soft water-solublegelating shells to form 8,0000 vaginal capsules, each capsule containing1000 mg of the formulation.

EXAMPLE 3

An antifungal capsule formation in accordance with the present inventionhaving the following composition was prepared as described below.

    ______________________________________                                        Ingredient              Amount (g)                                            ______________________________________                                        Nystatin* (100,000 USP units)                                                                         160                                                   Gelucire 35/10 (hydrogenated                                                  fat)                    7,840                                                 TOTAL                   8,000  g                                              ______________________________________                                         *Actual weight dependent on assay                                        

7,840 grams of gelucire 35/10 was heated to about 35° C. There after 160grams of nystatin was added and uniformly dispersed using a standardhomogenizer. Upon cooling to room temperature (about 3 hours), theso-formed mixture set to a gel. This formulation was thereafterencapsulated in soft, water-soluble, gelatin shells to form 8,000vaginal capsules, each capsule containing 1000 mg of the formulation.

EXAMPLE 4

An oral nystatin capsule formulation was made as described in Example 1and having the following composition.

    ______________________________________                                        Ingredient              Amount (g)                                            ______________________________________                                        Nystatin* (500,000 USP units)                                                                         700                                                   Mineral Oil, USP        2,782.5                                               Fumigated Silicon dioxide                                                     (Aerosil 200)           17.5                                                  TOTAL                   3,500   g                                             ______________________________________                                         *Actual weight dependent on assay                                        

This formulation was thereafter encapsulated in hard, water-solbule, twopiece gelatin shells to form 7,000 oral capsules, each capsulecontaining 500 mg of the formulation.

EXAMPLE 5

An oral nystatin capsule formulation was made as described in Example 2and having the following composition.

    ______________________________________                                        Ingredient              Amount (g)                                            ______________________________________                                        Nystatin (500,000 USP units)                                                                          700                                                   TWEEN 80                2,782.5                                               Fumigated Silicon dioxide                                                     (Aerosil 200)           17.5                                                  TOTAL                   3,500   g                                             ______________________________________                                    

This formulation was thereafter encapsulated in soft, water,water-soluble, gelating shells to form 7,000 oral capsules, each capsulecontaining 500 mg of the formulation.

EXAMPLE 6

An oral nystatin capsule formulation was made as described in Example 3and having the following composition.

    ______________________________________                                        Ingredient              Amount (g)                                            ______________________________________                                        Nystatin (500,000 USP units)                                                                          700                                                   Gelucire 35/10 (Hydrogenated                                                  fat)                    2,800                                                 TOTAL                   3,500  g                                              ______________________________________                                         This formulation was thereafter encapsulated in soft, water-soluble,     gelatin shells to form 7,000 capsules, each containing 500 mg of the     formalation.

COMPARITIVE EXAMPLE

A batch of solid nystatin vaginal tablets, in accordance with the priorart, having the following composition was manufactured as describedbelow.

    ______________________________________                                        Ingredient              mg/tablet                                             ______________________________________                                        Nystatin* (120,000 USP units)                                                                         24                                                    Ethylcellulose Type N-22                                                                              20                                                    Corn Starch USP         33                                                    Stearic Acid NF         22                                                    Lactose                 1,101                                                 TOTAL                   1,200  g                                              ______________________________________                                         *Actual weight dependent on assay                                        

The weighed quantities of the ingredients to make a 5,000 tablet batchwere transferred to a blender and thoroughly mixed until uniform andcompressed into tablets each weighing about 1200 mg. These tablets wereplaced in plastic bottles with plastic closures and stored at 20° C. and40° C. The potency of the nystatin tablets was checked and is expressedbelow as a percent of the initial potency.

    ______________________________________                                        Prior Art Vaginal Tablet Stability                                                         20° C.  40° C.                                                  120,000        120,000                                           Initial Potency                                                                            (USP Units)    (USP Units)                                       ______________________________________                                        l month      91%            82%                                               3 months     88%            73%                                               ______________________________________                                    

As a comparison the oral capsules as fabricated in Example 4 using twopiece hard gelatin capsules were tested under the same conditions. Theresults, which show a substantially improved stability for the nystatinover time and a reduced sensitivity to temperature are summarized below.

    ______________________________________                                        Nystatin Capsule                                                              (from Ex. 4)                                                                            -20° C.                                                                          4° C.                                                                          20° C.                                                                        32° C.                                                                       40 ° C.                       ______________________________________                                        Initial Potency                                                                         504,318   504,318 504,318                                                                              504,318                                                                             504,318                              (units)                                                                       1 month   96%       98%     99%    99%   99%                                  3 months  --        98%     98%    99%   99%                                  6 months  96%       96%     99%    96%   96%                                  9 months  --        96%     95%    97%   95%                                  ______________________________________                                    

Also, as a comparison, oral capsules as fabricated 2, 3, 5, and 6 weretested under the same conditions. The results, which show asubstantially improved stabililty for the nystatin over time and areduced sensitivity to temperature are summarized below.

    ______________________________________                                        Nystatin Stability*                                                                     Initial                                                                       Potency  1 month  3 months                                          ______________________________________                                        Example 1                                                                     4° C.           92%      96%                                           RT          105,000    94%      93%                                           40° C.          94%      93%                                           Example 2                                                                     4° C.           102%     100%                                          RT          96,100     99%      101%                                          40° C.          99%      97%                                           Example 3                                                                     4° C.           98%      99%                                           RT          99,100     102%     99%                                           40° C.          99%      98%                                           Example 4                                                                     4° C.           102%     101%                                          RT          513,000    104%     100%                                          40° C.          103%     101%                                          Example 5                                                                     4° C.           106%     106%                                          RT          507,000    103%     107%                                          40° C.          103%     101%                                          ______________________________________                                         *numbers represent USP units of activity                                 

What is claimed is:
 1. An antifungal capsule formulation suitable fororal or vaginal use comprising an antifungal or antibacterial agentsubject to oxidative or hydrolytic degradation in an amount of fromabout 0.1 to about 50 percent by weight of the total formulation; and anonaqueous carrier throughout which said agent is uniformly dispersed,thereby providing stability to said agent.
 2. The formulation of claim 1wherein said nonaqueous carrier is selected from the group consisting ofnonaqueous liquid surfactants and hydrogenated fats or mixtures thereof.3. The formulation of claim 2 wherein said carrier comprises anonaqueous liquid surfactant selected from the group consisting ofsorbitan mono-9-octadecenoate poly(oxy-1,2-ethanediyl) derivatives,oleaginous liquids and mixtures thereof.
 4. The formulation of claim 3wherein said oleaginous liquid is selected from the group consisting ofmineral oil, vegetable oils and mixtures thereof.
 5. The formulation ofclaim 3 wherein said nonaqueous carrier includes said nonaqueous liquidsurfactant in an amount of from about 90 to about 100 percent by weightof the total carrier.
 6. The formulation of claim 2 wherein saidnonaqueous carrier includes said nonaqueous liquid surfactant in anamount of from about 96 to about 100 percent by weight of the totalcarrier.
 7. The formulation of claim 1 wherein said nonaqueous carrieris a thixotropic gel.
 8. The formulation of claim 7 wherein said carrierfurther comprises a sufficient amount of gelling agent selected from thegroup consisting of silicon dioxide or fumigated silicon dioxide torender the carrier thixotropic.
 9. The formulation of claim 8 whereinsaid carrier includes gelling agent in an amount of from about 0.1 toabout 10 percent by weight of the total carrier.
 10. The formulation ofclaim 7 wherein said nonaqueous carrier comprises a nonaqueoushydrogenated fat.
 11. The formulation of claim 10 wherein the nonaqueouscarrier includes said fat in an amount of from about 90 to about 100percent by weight of the total carrier.
 12. The capsule formulation ofclaim 1 wherein said antifungal or antibacterial agent is selected fromthe group consisting of nystatin, amphotericin B, miconazole,ketoconazaole, econazole or griseofulvin, penicillins andcephalosporins.
 13. The formulation of claim 12 wherein said antifungalagent is nystatin.
 14. The formulation of claim 13 containing from about25,000 to about 1,000,000 USP units of nystatin.
 15. The formulation ofclaim 13 wherein the nystatin has a particle size of from about 1 toabout 50 microns.
 16. A vaginal antifungal capsule comprising aformulation which includes between about 2 and 4 percent by weight ofnystatin, between about 94 and 97 percent by weight of mineral oil andbetween about 1 and 2 percent by weight of silicon dioxide; saidformulation being encapsulated in a soft, water-soluble gelatin shell.17. An oral antifungal capsule formulation which includes between about15 and 25 percent by weight of nystatin, between about 73 and 84 percentby weight of mineral oil and between about 1 and 2 percent by weight ofsilicon dioxide.
 18. A method of treating vaginal candidiasis whichcomprises administering to the human vaginal cavity in need of suchtreatment the antifungal soft capsule of claim 16, including atherapeutically effective amount of said capsule formulation, such thatupon dissolution of the soft gelatin shell, said thixotropic gel carrierwill adhere to the vaginal mucous membrane thereby delivering saidantifungal agent thereto.
 19. A low temperature method of fabricatingantifungal capsules with enhanced stability comprising(a) forming aslurry by mixing a suitable amount of an antifungal or antibacterialagent in a nonaqueous liquid carrier; (b) encapsulating the so-formed,drug-containing slurry in a suitable shell; and (c) carrying out parts(a) and (b) in a substantially dry, room temperature environment. 20.The method of claim 19 wherein a gelling agent is added to the slurry inan amount sufficient to form a thixotropic gel.
 21. The method of claim19 wherein said antifungal or antibacterial agent is selected from thegroup consisting of nystatin, amphotericin B, miconazole, ketoconazole,econazole or griseofulvin, penicillins or cephalosporins.
 22. The methodof claim 21 wherein said antifungal agent is nystatin.
 23. The method ofclaim 22 wherein said nonaqueous liquid is selected from the groupconsisting of sorbitan mono-9-octadecenoate poly(oxy-1,2-ethanediyl)derivatives or oleaginous liquids and wherein said gelling agent isselected from the group consisting of silicon dioxide or fumigatedsilicon dioxide.
 24. The method of claim 23 wherein said oleaginousliquid is selected from the group consisting of mineral oil or avegetable oil.